Apparatus and method for delivery of antimicrobial during a transdermal sampling and delivery process

ABSTRACT

A device for introducing at least one antimicrobial in an exposed region of a user&#39;s skin caused while accessing interstitial fluid includes a substrate having thereon at least one electrically controllable microheating element including at least a microheater portion with multiple electrodes connected to the microheater portion for forming a micropore in the user&#39;s skin. A nanofiber mat loaded with at least one antimicrobial material is arranged on the substrate such that it contacts the user&#39;s skin and encircles an opening of the micropore formed by the microheating element. In a preferred embodiment, the at least one antimicrobial material is LL-37.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to and the benefit of similarlytitled U.S. Provisional Patent Application Ser. No. 62/200,421 filedAug. 3, 2015, the entire substance of which is incorporated herein byreference.

BACKGROUND

Medical sampling, monitoring and drug delivery systems and processescontinue to evolve with a focus on minimization of invasiveness to thepatient. By way of example, the following co-owned patents and patentapplications are directed to various transdermal sampling and deliverytechnologies and are incorporated herein by reference in theirentireties: U.S. Pat. Nos. 6,887,202, 7,931,592, 8,568,315 and U.S.application Ser. No. 14/036,966 directed to Systems and Methods forMonitoring Health and Delivering Drugs Transdermally; U.S. applicationSer. No. 13/459,392 directed to Electrochemical Transdermal GlucoseMeasurement System Including Microheaters and Process For Forming; U.S.application Ser. No. 13/835,696 directed to Microfluidic Systems ForElectrochemical Transdermal Glucose Sensing Using a Paper-Based or OtherWicking Substrate; and U.S. application Ser. No. 13/384,199 directed toMicrofluidic Systems for Electrochemical Transdermal Analyte SensingUsing a Capillary-Located Electrode (collectively, “Patent Documents”).

While the primary goal of these transdermal systems is to provideminimally invasive devices and processes for collecting and analyzingsamples, e.g., blood, interstitial fluid, for analytes and/or forproviding medications responsive thereto (e.g., transdermal drugdelivery), even a minimally invasive system can leave the accesslocation vulnerable to various microorganisms or microbes, e.g.,bacteria, fungi, viruses, which may reside on the user's skin and/or onthe devices. Such microorganisms can migrate into the body through theaccess location, e.g., micropore, causing a potential adverse (negative)response. Some of these microorganisms include drug-resistant bacteria,also called superbugs (e.g., MRSA, C-difficile) which are increasinglyresistant to known antibiotics.

Prior research has been conducted in the related area of preventingand/or treating in vivo bacterial infections at open wound sites, suchas open fracture sites, using nanocoatings on orthopedic implants. See,Li et al., Multilayer polypeptide nanoscale coatings incorporating IL-12for the prevention of biomedical device-associated infections,Biomaterials, Volume 30, Issue 13, May 2009, Pages 2552-2558 and Li etal., Evaluation of local MCP-1 and IL-12 nanocoatings for infectionprevention in open fractures. J. Orthop. Res. 28:48-54. But far lessinvasive devices and procedures can also increase user susceptibility tomicroorganisms.

Accordingly, there is a need in the art for an apparatus and process formitigating possible negative secondary effects resulting from the use ofminimally invasive medical sampling, monitoring and drug deliverydevices.

Additionally, the risk of infection at surgical and other wound sitesdressed with sutures and/or other closure materials remains an issue,particularly with the rise of antibiotic resistant super bugs in thehospital or other medical treatment settings. Accordingly, an on-goingneed exists for the mitigation of this infection risk.

In addition to the patents and patent applications listed above, thefollowing documents are incorporated herein by reference in theirentireties and are intended to provide examples of the skill in the artand supporting description for one or more aspects of the embodimentsdescribed and illustrated herein: J. W. Gatti et al., Using electrospunpoly(ethylene-oxide) nanofibers for improved retention and efficacy ofbacteriolytic antibiotics, Biomed Microdevices, October 2013, Volume 15,Issue 5, pp 887-893; Bio-Functionalized Nanofibers, Pan-AmericanAdvanced Studies Institute (PASI), Aug. 4-12, 2011; J. W. Gatti, UsingElectrospun Poly(ethylene-glycol) Nanofibers for Localized Delivery ofAntibiotics, Senior Thesis; Ball et al., Drug-Eluting Fibers for HIV-1Inhibition and Contraception, PLOS One, Vol. 7, Issue 11, November 2012;Vandamme et al., “A comprehensive summary of LL-37, the factotum humancathelicidin peptide,” Cellular Immunology 280, pgs. 22-35 (2012); andSong et al., “Multi-biofunction of antimicrobial peptide-immobilizedsilk fibroin nanofiber membrane: Implications for wound healing,” ActaBiomater. Volume 39, 15 July 2016, Pages 146-155.

SUMMARY OF THE EMBODIMENTS

In a first exemplary embodiment, a device for introducing at least oneantimicrobial in an exposed region of a user's skin caused whileaccessing interstitial fluid of a user includes a substrate havingthereon a mechanism for accessing the interstitial fluid of the user;and a nanofiber mat loaded with at least one antimicrobial material.

In a second exemplary embodiment, a hand-held device forelectrochemically monitoring an analyte in interstitial fluid of a userincludes: a first end configured to contact the skin of the user, thefirst end including a mechanism for ablating the skin of the user toform a micropore to access interstitial fluid and further including ananofiber mat formed thereon, the nanofiber mat including at least oneantimicrobial material; a cartridge connected to the first end andhaving disposed therein a plurality of disposable sensing elements forcontacting interstitial fluid from the micropore to monitor an analytetherein; and a second end connected electrically and mechanically to thecartridge and the first end for facilitating operation of the mechanismfor ablating the skin, dispensing of a disposable sensing element andmonitoring of the analyte.

In a third exemplary embodiment, a patch having multiple individuallycontrollable sites for accessing interstitial fluid of a user andmonitoring at least one analyte therein, includes a substrate havingformed thereon the multiple individually controllable sites eachincluding: a mechanism for producing a micropore in the user's skin andaccessing the interstitial fluid of the user and a nanofiber mat loadedwith at least one antimicrobial material; and an adhesive for adheringthe patch to the skin of the user.

BRIEF SUMMARY OF THE FIGURES

The Summary of the Embodiments, as well as the following DetailedDescription, is best understood when read in conjunction with thefollowing exemplary drawings:

FIGS. 1a and 1b show a first representative heating element withantimicrobial mat configuration in accordance with an embodiment herein;

FIGS. 1c-1e show a second representative heating element withantimicrobial mat configuration in accordance with an embodiment herein;

FIG. 2 shows a particular multiple use device having a heating elementwith antimicrobial mat configuration in accordance with an embodimentherein;

FIG. 3 shows a particular multiple use device having a heating elementwith antimicrobial mat configuration in accordance with an embodimentherein;

FIGS. 4a and 4b show a representative heating element with alternativeantimicrobial mat configurations in accordance with an embodiment hereinwherein multiple antimicrobial materials are incorporated in to the samemat; and

FIGS. 5a-5c show an exemplary hand-held device incorporating amicroheater in conjunction with an antimicrobial mat.

DETAILED DESCRIPTION

FIGS. 1a and 1b illustrate a singular microheating element 10 whichincludes resistive heater electrodes 12 a, 12 b which are connected by amicroheater portion 14 for generating a localized thermal pulse when anappropriate voltage is applied thereto. The resistive heater electrodes12 a, 12 b form a closed circuit and upon application of an appropriatevoltage for an approximate length of time thereto, act to ablate aportion of the stratum corneum 20 of the individual, creating amicropore 16 therein on the order of microns in diameter. Such ablation,though minimally invasive, makes the individual more susceptible at thesite of the micropore 16 to various microorganisms or microbes, e.g.,bacteria, fungi, viruses, which may reside on the user's skin or on aportion of the contacting instrument. Accordingly, the microheatingelement 10 further includes an annulus-shaped nanofiber mat 18 which hasbeen loaded with an antimicrobial, such as, for example LL-37. The widthof the annulus being on the order of approximately 5-25 μm. Themicroheating element 10 is formed on a substrate 22.

The applied voltage specifications, i.e., volts/time, may vary inaccordance with patient age and size. For example, devices used on adulthuman patients may be configured to apply 3V (with respect to ground)for, e.g., 30 msec, resulting in a rapid ablation of a portion of thepatient's stratum corneum creating an approximately 50 μm diametermicropore therein. Whereas, the same or a different device, may beconfigured for use with premature human patients where the stratumcorneum has minimal thickness. In this case, one skilled in the artrecognizes that the applied voltage, time and resulting pore diameterwould be reduced.

Further, while the specific representative embodiments described andillustrated herein include the nanofiber mat 18 as being part of themicroheating element 10, one skilled in the relevant art understandsthat variations which provide for the nanofiber mat 18 being in closeproximity to the resulting micropore 16, but not necessarily on themicroheating element 10, fall well within the scope of the presentembodiments. For example, referring to FIGS. 1c-1e , a differentconfiguration and ordering of elements includes microheating element 10having resistive heater electrodes 12 a, 12 b which are connected by amicroheater portion 14 formed on a first substrate 22 a having a holetherethrough at the point adjacent the microheater portion 14. FIG. 1dshows a second substrate 22 b including an antimicrobial nanofiber mat(or layer) 18 thereon, with a hole therethough having a diameterslightly larger than the hole in the first substrate 22 a. And in FIG.1e , the first and second substrates are aligned back-to-back with theholes aligned to form the final transdermal device. The gap height hfrom the microheater portion 14 and the skin, i.e., stratum corneum 20is small, such that the heat from the microheater portion 14 issufficient to cause the desired ablation and form micropore 16.

Additional details regarding the formulation, layout, dimensions andoperation of the microheating element 10 are described in the co-ownedpatents and patent applications (collectively, “Patent Documents”)listed in the Background section above. Multiple microheating elements10 may be used in an array as discussed in the Patent Documents, whereinmultiple individual microheating elements 10 each having a nanofiber mat18 on or associated therein are included in an array. The array may beincluded on a substrate, e.g., patch, wherein each of the individualmicroheating elements 10 is individually controllable/usable, thusresulting in multiple micropores over the course of time and use of thearray.

FIGS. 2 and 3 illustrate portions of exemplary multiple use devices,which include multiple individually controllable sites (S₁, S₂, S₃ . . .S_(x)), each site including components similar to those illustrated inFIGS. 1a and 1b or equivalents thereof. Use of each of S₁, S₂, S₃ . . .S_(x) results in a micropore which, as discussed previously, makes theindividual more susceptible at the site of the micropore to variousmicroorganisms or microbes, e.g., bacteria, fungi, viruses, which mayreside on the user's skin or on a portion of the contacting instrument.Accordingly, as illustrated, individual nanofiber mats 18 areincorporated at each site (S₁, S₂, S₃ . . . S_(x)), adjacent to themicropore and in contact with the user's skin. Alternating with thenanofiber mats is adhesive A for adhering the multiple use device to theskin of the user.

FIGS. 2 and 3 illustrate particular devices wherein the microheaterportion 14 acts to both create the micropore and to release aphysiological compatible solution, e.g., saline, from a reservoir in thedevice which mixes with interstitial fluid released from micropore andtravels up a detection path in the device to a detector (not shown, butdescribed in one or more Patent Documents). The device provides for“on-demand” analysis and the inclusion of the nanofiber mat 18 withantimicrobial provides added protection to the user at the spent sites,e.g., S₁. A physiological solution is preferably expelled onto theexposed viable epidermis and recovered into the transport capillary. Oneskilled in the art recognizes that the micro-heater and thephysiological solution seal may be the same or different; the heater andseal may, therefore, be electrically connected either in series orparallel. Additionally, the physiological compatible solution may or maynot contain one or more drugs.

Alternatively, the device may be a single-use device. Whether themicroheating element is part of a single-use device or a multi-usedevice, the effectiveness of the nanofiber mat 18 or more specifically,the antimicrobial, may be enhanced by keeping the device in place for apredetermined amount of time, e.g., at least 2 hours, or an approximateamount of time calculated for the micropore 16 in the stratum corneum tobegin closing up.

A description of exemplary processes for formation of the nanofiber matfor use in the embodiment described herein may be found in one or moreof the documents listed in the section Documents Incorporated byReference. The immobilization of antimicrobial peptides and peptidemotifs on nanofiber membranes has been achieved and the effectiveness ofthe antimicrobial nanofiber membranes as both an antibiotic and a woundhealing facilitation material has been determined. In a specificexemplary embodiment, the nanofiber mat 18 may be formed usingelectrospinning techniques to generate nanofibers having varyingdiameters, e.g., 100-500 nm, from a solution of poly(ethylene-oxide)(PEO) and the antimicrobial peptide, LL-37 as discussed in detail in J.W. Gatti et al., Using electrospun poly(ethylene-oxide) nanofibers forimproved retention and efficacy of bacteriolytic antibiotics, BiomedMicrodevices, October 2013, Volume 15, Issue 5, pp 887-893.

The antimicrobial LL-37 is selected as the exemplar microbial herein forits broad bacteria killing ability. More specifically, LL-37 has beenshown to kill the following bacteria as discussed in Vandamme et al., “Acomprehensive summary of LL-37, the factotum human cathelicidinpeptide,” Cellular Immunology 280, pgs. 22-35 (2012): Bacillusanthracis; Enterococcus faecalis; Group A streptococcus; Group BStreptococcus; Lactobacillus casei; Listeria monocytogenes; Micrococcusluteus; Nocardia sp.; Propionibacterium acnes; Staphylococcus aureus;Streptococcus mutans; Streptococcus pneumonia; Borrelia spp.;Mycobacterium bovis; Mycobacterium smegmatis; Mycobacteriumtuberculosis; Achromobacter xylosoxidans; Acinetobacter baumannii;Aggregatibacter actinomycetemcomitans; Brucella suis; Burkholderiapseudomallei; Burkholderia cepacia; Burkholderia thailandensis;Capnocytophaga spp.; Escherichia coli; Francisella novicida;Fusobacterium nucleatum; Haemophilus influenza; Helicobacter pylori;Klebsiella pneumonia; Leptospira interrogans; Mannheimia haemolytica;Pasteurella multocida; Porphyromonas circumdentaria; Porphyromonasgingivalis; Prevotella intermedia; Prevotella loescheii; Prevotellamelaninogenica; Pseudomonas aeruginosa; Salmonella sp.; Shigella sp.;Stenotrophomonas maltophilia; Tannerella forsythia; Treponema denticola;Treponema pallidum and Yersinia pestis.

One skilled in the art readily recognizes that other antimicrobials maybe used, either alone, or in combination with LL-37 to cover a widerrange of bacteria. FIGS. 4a-4b illustrate an annulus-shaped nanofibermat which includes multiple antimicrobials (AM1, AM2, . . . AMX) loadedtherein.

The incorporation of an antimicrobial is also contemplated with respectto, e.g., a hand-held device for electrochemically monitoring an analytein interstitial fluid of a user, such as that disclosed in co-owned U.S.patent application Ser. No. 13/835,696. Components of an exemplarydevice 34 are illustrated in FIGS. 5a-5c . The device includes aplurality of sensing elements 36, each comprising a system ofelectrodes, as described above, on an individual portion of apaper-based or other wicking substrate. Each individual sensing elementhas a system of conductive elements 37 connectable to a controllablevoltage source 38 within the device, and each comprises at least oneelectrode 39 modified with a sensing material, such as glucose oxidase(GOx), for measuring the level of the analyte in a fluid which contactsthe sensing element.

Although not shown, connective elements located e.g. in the inner wallof device 34 can serve to place elements 37, 39, and/or 50 (as describedbelow) in contact with the controllable voltage source 38.

With further reference to FIGS. 5a-5c , the device preferably includes ahandle region 40 attached to an end region 42 having an open tip 44. (Inpractice, the tip could be a closed tip which is openable prior to use.)In a specific embodiment of the hand-held device, the end region 42 maybe single-use cartridge that may be discarded and replaced as needed.The end region includes a storage region 46, for containing apredetermined number of sensing elements 36, adjacent the open tip. Theperiphery 48 of the open tip comprises a conductive microheater element50, which is connectable to the voltage source 38 within the device, anda ring of antimicrobial mat 54 deposited thereon. The antimicrobial mat54 may of sufficient thickness, e.g. nanometers to millimeter, to lastthrough the use of all of the predetermined number of sensing elements36 in the cartridge, i.e., end region 42. The location of theantimicrobial mat 54 may be adjacent to the outer rim of the microheaterelement 50 as shown in FIG. 3b or in a stacked configuration as shown inFIG. 5c , so long as the antimicrobial mat 54 is contacting the skin ofthe user. Additional details regarding configurations and operation ofthe hand-held device are described in U.S. patent application Ser. No.13/835,696 which is incorporated herein by reference in its entirety.

While the particular examples above are directed to certain exemplarytransdermal devices, one skilled in the art appreciates that theantimicrobial nanofiber mat or coating may be incorporated into othermedical equipment that invades the body, including, but not limited tosyringes, catheters, etc.

As referenced briefly in the Background, the risk of infection atsurgical and other wound sites dressed with sutures and/or other closurematerials is an on-going concern. The antimicrobial nanofiber materialsreferenced above may form or be incorporated into various dressingsincluding, but not limited to biodegradable fibrous mesh, biodegradablesuture (e.g., a polymer) or non-biodegradable suture (e.g., silknanofibers) containing LL-37 or other antimicrobial. As with thenanofiber mats described herein, these dressings form a barrier toforeign bodies.

The invention claimed is:
 1. A device for introducing at least oneantimicrobial in an exposed region of a user's skin caused whileaccessing interstitial fluid of a user comprising: a first substratehaving thereon multiple, individually electrically controllablemicroheating elements including at least a microheater portion withmultiple electrodes connected to the microheater portion for accessingthe interstitial fluid of the user, the first substrate includingmultiple first holes therethough which are aligned with the microheaterportion of each of the microheating elements; and a second substratehaving a nanofiber material containing at least one antimicrobialapplied thereto in the form of multiple individual annulus-shapednanofiber mats, the second substrate further including multiple secondholes therethrough which are aligned with the microheater portion ofeach of the microheating elements, wherein each of the multipleannulus-shaped nanofiber mats surrounds one of the multiple secondholes; the second substrate further including an adhesive materialapplied between each of the nanofiber mats to adhere the device to theuser's skin; wherein the nanofiber material, the adhesive material, thesecond substrate, the first substrate and the microheating elements arearranged in the following order in the device: first, the nanofibermaterial and the adhesive material which are configured to contact theuser's skin; second, the second substrate; third, the first substrate;and fourth, the microheating elements.
 2. The device of claim 1, whereinone of the at least one antimicrobial is LL-37.
 3. The device of claim1, wherein the nanofiber mat includes the at least one antimicrobial andat least one additional antimicrobial material therein.
 4. The device ofclaim 3, wherein the at least two antimicrobial materials are arrangedin individual rings comprising the annulus-shaped nanofiber mat.
 5. Thedevice of claim 1, wherein each annulus-shaped nanofiber mats has awidth of between 5 to 25 μm.